Lung cancer is a cancer having the highest incidence in the world. In China, the incidence of lung cancer ranks first among all cancers and it is also a cancer having the highest morbidity and mortality.
In Chinese patients with lung cancer, 30% of patients have the EGFR mutation, wherein L858R and exon 19 deletion mutations account for more than 90% and these patients are more sensitive to EGFR inhibitors. The existing first generation EGFR inhibitors in market such as erlotinib and gefitinib have good treatment effects on these patients and can make the tumors of more than 60% of the patients shrink, thereby significantly prolonging the progression-free survival of patients. However, drug-resistance develops within 6-12 months for the most majority of patients, and the first-generation EGFR inhibitors are no longer effective, while no drugs are available to these patients currently. It has been found in clinic that EGFR T790M mutation was present in 50% of the patients who developed resistance to the first-generation EGFR inhibitors. The first-generation EGFR inhibitors, erlotinib and gefitinib, were greater than 3 uM in the T790M mutant cell line H1975 and almost have no activity.
Currently the second-generation irreversible pan-EGFR inhibitor, alfatinib, has been approved for the market. This drug has significantly better treatment effect on patients with EGFR mutation lung cancer compared with the first-generation EGFR inhibitors. However, the second-generation inhibitors also have a strong inhibitory activity on wild-type EGFR. The inhibitory activity on wild-type EGFR is significantly higher than that on the resistant T790M mutation. The side effects such as rash and the like are serious and it has poor treatment effect on drug-resistant patients. Only a small proportion of the patients resistant to first-generation EGFR inhibitors respond to this kind of drugs.
In order to increase the inhibitory activity against EGFR T790M resistance mutant while reduce the inhibitory activity against wild-type EGFR, developing third-generation EGFR mutant selective inhibitors with higher activity, better selectivity and lower toxicity is of great significance.